Insulin is a hormone that is necessary for normal carbohydrate, protein and fat metabolism in mammals. Insulin is known to bind to the extracellular domain (.alpha.-subunits) of its specific receptor. Following insulin binding, conformational changes in the insulin receptor lead to autophosphorylation of the intracellular .beta.-subunits and stimulation of the receptor's intrinsic tyrosine kinase activity and activation of insulin signal transduction pathway. The activated insulin receptor tyrosine kinase phosphorylates several intermediate substrates (e.g. IRS-1 and SHC). These proximal events lead to activation of additional signaling intermediates such as PI-3-kinase and MAP kinase. Through an unknown series of additional steps, modulation of key cellular components (e.g. glucose transporter translocation, activation of glycogen synthase, inhibition of gluconeogenic enzymes) coordinate stimulation of glucose disposal and inhibition of hepatic glucose output. Considerable evidence suggests that insulin receptor tyrosine kinase activity is essential for many, if not all of the biological effects of insulin. However, the precise biochemical mechanisms linking receptor kinase-mediated tyrosine phosphorylation to the regulation of cellular metabolic pathways are not completely defined.
Two major forms of diabetes mellitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization, and patients with Type I diabetes are dependent on exogenous insulin for survival. Type II diabetes, or non-insulin-dependent diabetes (NIDDM), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin (i.e. insulin resistance). Insulin resistance is a major susceptibility trait for NIDDM and is also a contributing factor in atherosclerosis, hypertension, lipid disorders and polycystic ovarian syndrome.
Over time, many individuals with NIDDM show decreased insulin production, which requires supplemental insulin for adequate blood glucose control, especially during times of stress or illness. An exogenous insulin regimen is often required in the treatment of secondary diabetes, i.e., diabetes occurring in relation to other disease states such as pancreatic disease. Insulin is also used in some cases of gestational diabetes to obtain optimum blood glucose control. The conventional route of insulin administration is subcutaneously via a needle and syringe. Continuous subcutaneous insulin infusion with an infusion pump is an alternative to conventional injection therapy for achieving normalized levels of blood glucose.
Conventional treatments for NIDDM, which have not changed substantially in many years, have significant limitations. While physical exercise and a reduction in dietary intake of calories could improve the diabetic condition, compliance with this treatment is generally poor. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide, glipizide) which stimulate the pancreatic .beta.-cells to secrete more insulin, or by injection of insulin after the response to sulfonylureas fails, will result in insulin concentrations that stimulate even highly insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from these last two treatments, and increasing insulin resistance due to the even higher plasma insulin levels could theoretically occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea, respectively.
Thiazolidinediones (glitazones) have been recently described as a class of compounds with a mechanism of action which ameliorates many symptoms of NIDDM. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several NIDDM animal models, resulting in the correction of elevated plasma levels of glucose, triglycerides and nonesterified fatty acids without the occurrence of hypoglycemia. However, undesirable effects associated with the glitazones have occurred in animal and human studies, including cardiac hypertrophy, hemadilution and liver toxicity.
Accordingly, there exists a continuing need for novel therapeutic agents for ameliorating the symptoms of diabetes mellitus, particularly for controlling the blood glucose level in patients, and for the prevention of the onset of diabetes. In addition, there is a need for new therapeutic agents for treating or overcoming insulin resistance in cases where it contributes to the pathogenesis of diseases or disorders.